Available evidence implicates genetics as a major risk factor in Alzheimer disease. Multiple reports of molecular and cellular abnormalities in non-neural tissues including cultured cells suggest that the expression of the predisposing gene(s) is not restricted to the nervous system. Previous studies have indicated changes in glucose and energy metabolism in both brain and cultured skin fibroblasts in Alzheimer disease. This project will elucidate the bases of these changes in cultured cells. Initial studies will test whether alterations of glucose metabolism, similar to those already identified in preliminary studies, distinguish between fibroblasts from groups of affected individuals and unaffected older members of the large Alzheimer kindreds available to us. Those aspects of the complex metabolic pathways of glucose and glutamine primarily contributing to the observed alterations will be determined from the relative incorporation of radiolabelled substrates into C02 and lactate and from direct measures of mitochondrial changes using oxygen uptake. Based on the results of these studies, specific metabolites and enzymes will be assayed to test whether changes are attributable to identifiable defects of individual components within the affected pathways. The effect of the metabolic changes on cellular function (which could ultimately compromise cell survival) will be determined from the content of energy- related metabolites (adenine nucleotides and phosphocreatine) and critical metabolic parameters (from the above studies) under normal conditions and during metabolic "stress" (in the presence of uncoupling agent or altered substrate availability). 2- Deoxyglucose uptake (as a convenient marker of glucose metabolism) or other more sensitive parameters identified in the above studies will be used to determine whether metabolic defects in the Alzheimer fibroblasts are an exacerbation of normal age-related changes, and whether similar changes are seen in other neurological diseases. The identification of diagnostic markers in Alzheimer cells and/or the identification of specific metabolic abnormalities would be a major advance in understanding the pathogenesis of this disease and may be an important step in the development of specific treatments.